Perini J A, Struchiner C J, Silva-Assunção E, Santana I S C, Rangel F, Ojopi E B, Dias-Neto E, Suarez-Kurtz G
Divisão de Farmacologia, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
Clin Pharmacol Ther. 2008 Dec;84(6):722-8. doi: 10.1038/clpt.2008.166. Epub 2008 Aug 27.
A dosing algorithm including genetic (VKORC1 and CYP2C9 genotypes) and nongenetic factors (age, weight, therapeutic indication, and cotreatment with amiodarone or simvastatin) explained 51% of the variance in stable weekly warfarin doses in 390 patients attending an anticoagulant clinic in a Brazilian public hospital. The VKORC1 3673G>A genotype was the most important predictor of warfarin dose, with a partial R(2) value of 23.9%. Replacing the VKORC1 3673G>A genotype with VKORC1 diplotype did not increase the algorithm's predictive power. We suggest that three other single-nucleotide polymorphisms (SNPs) (5808T>G, 6853G>C, and 9041G>A) that are in strong linkage disequilibrium (LD) with 3673G>A would be equally good predictors of the warfarin dose requirement. The algorithm's predictive power was similar across the self-identified "race/color" subsets. "Race/color" was not associated with stable warfarin dose in the multiple regression model, although the required warfarin dose was significantly lower (P = 0.006) in white (29 +/- 13 mg/week, n = 196) than in black patients (35 +/- 15 mg/week, n = 76).
一种包含遗传因素（维生素K环氧化物还原酶复合体亚单位1基因[VKORC1]和细胞色素P450 2C9基因[CYP2C9]基因型）和非遗传因素（年龄、体重、治疗指征以及与胺碘酮或辛伐他汀的联合治疗）的给药算法，解释了巴西一家公立医院抗凝门诊390例患者稳定的每周华法林剂量变异的51%。VKORC1 3673G>A基因型是华法林剂量最重要的预测因子，偏决定系数（R²）值为23.9%。用VKORC1双倍型取代VKORC1 3673G>A基因型并未增加该算法的预测能力。我们认为，与3673G>A处于强连锁不平衡（LD）状态的其他三个单核苷酸多态性（SNP）（5808T>G、6853G>C和9041G>A）同样是华法林剂量需求的良好预测因子。该算法在自我认定的“种族/肤色”亚组中的预测能力相似。在多元回归模型中，“种族/肤色”与稳定的华法林剂量无关，尽管白人患者（29±13毫克/周，n = 196）所需的华法林剂量显著低于黑人患者（35±15毫克/周，n = 76）（P = 0.006）。
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